Nathaniel H. Robin

Opitz G/BBB syndrome: Clinical comparisons of families linked to Xp22 and 22Q and a review of the literature

Opitz G/BBB syndrome (OS) was first described in 1969 as two separate disorders, the G syndrome, and the BBB syndrome. Since the time, it has become apparent that the BBB and the G syndromes are in fact a single entity, now named the Opitz G/BBB syndrome. However, our recent molecular genetic mapping studies have shown that OS is an heterogeneous disorder, with loci at Xp22 and 22q. To determine if there are any discernible phenotypic differences between the X-linked and the autosomal dominant forms of OS, we have conducted a clinical study of the families who participated in the linkage analysis. In addition, we compared the clinical findings in the study families with those who have been reported in the literature. We found that anterveted nares and posterior pharyngeal cleft were seen only in X-linked families. However, all other manifestations of OS, such as hypertelorism, swallowing difficulties, hypospadias, and developmental delay, were seen in both groups. Therefore, while OS is heterogenous, significant clinical overlap is present between the two groups, and it is presently impossible to assign a specific phenotype to the X-linked or the autosomal type of OS. Furthermore, we found that for individuals in our study families who carried the OS allele, the incidence of major abnormalities was lower than what is reported in the literature.

Molecular characterization and delineation of subtle deletions in de novo "balanced" chromosomal rearrangements

Abstract To test the hypothesis that the phenotypic abnormalities seen in cases with apparently balanced chromosomal rearrangements are the result of the presence of cryptic deletions or duplications of chromosomal material near the breakpoints, we analyzed three cases with apparently balanced chromosomal rearrangements and phenotypic abnormalities. We characterized the breakpoints in these cases by using microsatellite analysis by polymerase chain reaction and fluorescence in situ hybridization analysis of yeast artificial chromosome clones selected from the breakpoint regions. Molecular characterization of the translocation breakpoint in patient 1 [46,XY,t(2;6)(p22.2;q23.1)] showed the presence of a 4- to 6-Mb cryptic deletion between markers D6S412 and D6S1705 near the 6q23.1 breakpoint. Molecular characterization of the proximal inversion 7q22.1 breakpoint in patient 2 [46,XY,inv(7)(q22.1q32.1)] revealed the presence of a 4-Mb cryptic deletion between D7S651 and D7S515 markers. No deletion or duplication of chromosomal material was found near the breakpoints in patient 3 [46,XX,t(2;6)(q33.1;p12.2)]. Our study suggests that a systematic molecular study of breakpoints should be carried out in cases with apparently balanced chromosomal rearrangements and phenotypic abnormalities, because cryptic deletions near the breakpoints may explain the phenotypic abnormalities in these cases.

Child with mosaic variegated aneuploidy and embryonal rhabdomyosarcoma

We report on a 7-year-old boy with mosaic variegated aneuploidy (MVA) who developed embryonal rhabdomyosarcoma of the soft palate. This patient is the 11th case report of MVA and represents further documentation of the true existence of this rare mitotic mutant. Clinical findings share similarities to those previously described patients including microcephaly and growth retardation as the two most common abnormalities. Notably, mental retardation is not universally present. Results of serial cytogenetic analyses performed on somatic and neoplastic tissues are reviewed and compared with those of other previously reported patients. We postulate that mosaic variegated aneuploidy is causally related to the development of rhabdomyosarcoma in our patient. This is the first report of a patient with MVA who developed cancer and suggests that these patients may be at risk for malignancy and require long-term follow-up and cancer surveillance.

Microcephaly-lymphedema-chorioretinal dysplasia: a unique genetic syndrome with variable expression and possible characteristic facial appearance.

We report on a follow-up examination of a family with microcephaly and lymphedema. The finding of chorioretinal dysplasia with variable visual deficit in multiple relatives, which was not previously discovered, supports the concept of microcephaly, lymphedema, and chorioretinopathy as being a single autosomal dominant genetic entity with variable expression. We recommend that fundoscopic examination be performed in all patients with microcephaly with or without lymphedema.

Delay in Diagnosis of Williams Syndrome

Williams syndrome (WS) is a well-known genetic disorder with a variable phenotype. In many cases, physical manifestations are subtle and may not be apparent at an early age, making diagnosis difficult in infants and young children who lack classic manifestations such as supravalvular aortic stenosis and hypercalcemia. Clinical suspicion is essential because the diagnostic genetic finding is not detectable on routine chromosomal analysis. Furthermore, early diagnosis allows for earlier detection and treatment of developmental, behavioral, and medical problems. In an effort to understand how and why individuals with WS are diagnosed, we conducted a survey-based study of parents of WS children. Packets containing a cover letter, consent form, parental survey and preaddressed stamped envelope were distributed to parents of children with WS. The survey included questions concerning initial diagnosis, WS findings present, medical specialists involved, and tests performed. Forty-six completed surveys were returned for analysis. The mean age at diagnosis was 3.66 years (SD 4.13). The mean age at which there were initial concerns was 0.98 year (SD 1.24) resulting in a mean delay in diagnosis of 2.77 years (SD 4.10). In addition, the involvement of a geneticists correlated with earlier diagnosis (2.26 years vs. 5.09 years without geneticist involvement, p = 0.03) and fewer tests ordered (5.2 vs. 8.2 in the nongeneticist group, p=0.0006). We observed a significant delay in the diagnosis of WS. Of note, the involvement of a geneticist was associated with earlier diagnosis and reduced number of tests.

Severe oculocerebrocutaneous (Delleman) syndrome: overlap with Goldenhar anomaly.

Oculocerebrocutaneous syndrome (OCCS), or Delleman syndrome, is a multiple congenital anomaly syndrome characterized by orbital cysts, cerebral malformations, and focal dermal hypoplasia [Delleman and Oorthuys, 1981, Clin Genet 19:191-198; Delleman et al., 1984, Clin Genet 25:470-472]. Two previous reports presented children having what is suggested as the more severe form of the OCCS syndrome who also had anophthalmia, congenital hydrocephalus, and cleft lip and palate [Leichtman et al., 1994, Am J Med Genet 50:39-41; Angle and Hersh, 1997, Am J Med Genet 68:39-42]. We report on a third case of severe OCCS, an infant girl with a similar constellation of findings and additional anomalies including lateral facial cleft, vertebral anomaly, and ventricular septal defect. The additional findings in our patient highlight the phenotypic overlap of OCCS and the Goldenhar anomaly, an overlap previously noted by Delleman and Oorthuys [1981], and others [Al-Gazali et al., 1988, J Med Genet 25: 773-778]. We suggest that the minimal diagnostic criteria for Delleman syndrome include central nervous system cyst or hydrocephalus, orbital cysts or microphthalmia, and focal skin defects.

Adult with an interstitial deletion of chromosome 10 [del(10)(q25.1q25.3)]: Overlap with Coffin-Lowry Syndrome

We recently evaluated a mentally retarded 48 year old man found to have a cytogenetic deletion of chromosome 10 [46,XY,del(10) (q25. 1q25.3)]. Of interest, he shares many clinical findings with those described in Coffin-Lowry syndrome (CLS). These include severe mental retardation, short stature and a coarse facial appearance with widely spaced eyes, and patulous lips. He also had an extra transverse hypothenar crease, a finding that is seen in CLS. Furthermore, he has characteristic radiographic hand findings described in 95% of patients with CLS. The CLS gene, located at Xp22. 2, has recently been identified, and mutations in the Rsk-2 gene have been identified in several CLS patients. Rsk2 is part of a gene family implicated in cell cycle regulation through the mitogen-activated protein (MAP) kinase cascade. None of the currently recognized components of this pathway maps to the region deleted in our patient, nor are we able to identify any likely candidate genes in the deleted region, although several G protein coupled receptors have been cloned from the region. This patients findings have some overlap with those seen in CLS, suggesting that a gene involved in MAP kinase signaling may be present in the deleted region of chromosome 10q25.1-25.3. Patients with a phenotype consistent with CLS, but lacking a family history suggestive of an X-linked disorder, should be evaluated with chromosome analysis paying particular attention to the region 10q25.

Cardiomyopathy in Coffin–Lowry syndrome

Coffin–Lowry syndrome (CLS) is a rare but well‐documented X‐linked disorder characterized by small size, developmental delay/mental retardation, and characteristic facial and skeletal findings in affected males. The phenotype in affected females is far more variable and can include developmental differences, obesity, and characteristic facial and skeletal differences. Cardiac anomalies are reported in less than 20% of affected males, with cardiomyopathy being one of the rare but reported complications of this disorder. However, cardiomyopathy is not well characterized in CLS. Here, we report on a 14‐year‐old boy with physical and developmental findings consistent with CLS who presented with a relatively sudden onset of signs of congestive heart failure due to a restrictive cardiomyopathy; an endomyocardial biopsy demonstrated non‐specific hypertrophic myocyte alterations consistent with cardiomyopathy. This is the first description of the histology and electron microscopy of cardiomyopathy in CLS.

Clinical and locus heterogeneity in brachydactyly type C

Brachydactyly type C is characterized by shortness of the second and fifth middle phalanges and the first metacarpal. It is inherited as an autosomal dominant trait, and is noted for its widely variable clinical phenotype both within and between families. In most families involvement is limited to the hands. However, in some families additional skeletal and non-skeletal findings have been reported. We report on 12 affected members from a 5 generation kindred that segregates a brachydactyly type C phenotype. All affected individuals had shortness principally affecting the second and fifth phalanges and first metacarpal. However, the metacarpal-phalangeal profile indicated that other digital elements were short as well. In addition, one affected individual had a bilateral Madelung deformity, but none had foot involvement. No other non-skeletal findings cosegregated with brachydactyly in this family. Recently, a gene for brachydactyly type C has been localized to 12q24. This was done by studying a large kindred first reported by Haws [1963], which manifests both hand and foot anomalies. Here we present linkage data which excludes the 12q24 locus in our kindred, indicating locus heterogeneity as one explanation for the interfamilial variability described in brachydactyly type C.

Genetic Testing for Deafness--GJB2 and SLC26A4 as Causes of Deafness.

UNLABELLED Recent advances in the molecular biology of hearing and deafness are being transferred from the research laboratory to the clinical arena. This transfer of knowledge will enhance patient care by making the diagnosis of hereditary deafness easier; however physicians and audiologists must clearly identify that subset of the deaf and hearing populations best served by this knowledge. It is also essential for physicians and audiologists to understand the limitations of genetic testing for deafness, and it is imperative that these limitations be appropriately explained to patients and their families. LEARNING OUTCOMES The reader will be introduced to the concept of genetic testing for deafness. Two genes that make appreciable contributions to the autosomal recessive non-syndromic deafness (ARNSD) genetic load will be reviewed, GJB2 and SLC26A4. In addition, the unique aspects of genetic counseling for deafness and recurrence chance estimates are explained.